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TOXICOLOGY OF HYDROGEN SULFIDE R. 1. Reiff enstein Department

of Pharmacology, University of Alberta, Edmonton, Alberta, Canada

T6G 2H7

William C. H ulbert

Pul monary Defence Group , Department of Medicine, University of Alberta, Edmon­ ton, Alberta, Canada T6G 2EI Sheldon H. Roth Division of Toxicology, Department of Pharmacology and Therapeutics, University of Calgary, Calgary, KEY WORDS:

Alberta, Canada

T2N 4Nl

neurological toxicity, lung, airway, development and growth, forensic analysis

INTRODUCTION Historical Background It is almost 300 years since the first description of hydrogen sulfid� (H2S) toxicity ( 1). There have, however, been few reviews and only one research conference (2) on H2S toxicity. Numerous governmental agencies concerned with occupational health or the environment have at various times prepared documents related to regulation of H2S exposure (e.g. 3, 4). An excellent history of the early experience with H2S appeared in the recent conference proceedings (5). A review in 1984 (6) included a bibliography of almost 1300 references, 196 of which were cited in the text. The general opinion was that sulfide inhibited oxidative enzymes in a manner similar to 109

0362- 1642/92/04 15-0 109$02.00

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cyanide, particularly enzymes involved with oxidative phosphorylation, but it must be concluded that additional processes are operating. Therapeutic mea­ sures have been suggested that follow the pattern used for the treatment of cyanide poisoning. However, animal experiments have not proved their validity for postexposure therapy, and clinical reports are still scarce. Recent advances have been made in the diagnosis of H2S poisoning, teratogenicity, and neurological and respiratory effects and have opened new possibilities for therapy. H2S poisoning is still a problem because of widespread environmental and occupational exposure from industrial activities, e.g. paper pulp mills, heavy­ water production, urban sewers, and farming, to name but a few of the more than 70 identified commercial sources. H2S is the predominant sulfur con­ taminant of natural gas and ranges in concentration from 90%. At least three epidemiological studies have recently addressed the health of populations exposed to this toxic gas (7-9). Physicochemical Properties H2S is a colorless gas heavier than air (d 1.19) with a molecular weight of 34.08 (10). It Is the sulfur analog of water. It can be oxidized by a variety of agents to form sulfur dioxide (S02), sulfates such as sulfuric acid, and elemental sulfur (these products also have toxicological implications). One gram of H2S will dissolve in 242 ml of H20, 94.3 ml of absolute etl!anol, or 48.5 ml of diethyl ether at 20oe. Because of its lipid solubility, it easily penetrates biological membranes. H2S evaporates from aqueous solutions (vapor pressure 18.75 x 105 Pa). An aqueous solution will dissociate (see Equation 1), yielding a hydrosulfide anion and sulfide ion; the two pKa values are 7.04 and 11.96, respectively. At a physiological pH of 7.4, approximately one-third of fhS exists as the undissociated form and two-thirds as the hydrosulfide anion. Some useful conversion factors for H2S are as follows: 1% volume 10,000 ppm, I mg liter-1 717 ppm (STP), and 1 ppm 1.4 mg m-3 =




2 H2S' � H+ + HS- � 2H+ + S -



Species Comparison The effects of acute and chronic exposure to H2S in many vertebrates and invertebrates have been investigated from three different points of view: lethality, on commercially valuable species, and mechanism of adaptation. The reader is directed to reviews on this subject (4, 6, 11, 12) . Briefly, lethality data for humans, dogs, cows, goats, monkeys, mice, guinea pigs, and rats are very similar, probably because the effect of H2S on eukaryotic cells is similar (see ref. 11 for a discussion). Table 1 shows the effects of H2S



Human physiologic responses t o exposure t o hydrogen sulfidea

Concentration of H2S

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mg m-3

Physiological responses Odor threshold

0.003 - 0.02

0 . 0042- 0.028



Obvious unpleasant odor



Strong offensive odor ("rotten eggs")



Sickening sweet odor



Conjunctival irritation


70 - 1 40

1 00-200


Loss of smell (olfactory fatigue)b

Irritation of respiratory tract

150 -200

2 1 0-280

Olfactory paralysisb


350 -700

Pulmonary edema









respiration, amnesia, unconsciousness ("knockdown") 500 - 1 000


Respiratory paralysis leading to death, immediate collapse, neural paralysis, cardiac arrhythmias, death

aAdapted from Beauchamp et al (6) and other sources (2. 4. 108). bOata require reevaluation because they are based on recollection of "knockdown" victims. who are known to have memory deficits (5).

on humans. There are some anomalies in the reported findings. Guinea pigs, but not rats, were reputed to die from exposure to 1 00 ppm of H2S. This may be related to the fact that guinea pigs have a more extensive nasal labyrinth, are obligate nose breathers, and did not evolve in a high-H2S atmosphere (sewers) like rats did (see 5). In obligate nose breathers, cellular damage, exfoliation, and mucus secretion cause the nasal passages to plug up, and the animals simply cannot breathe and hence die from lack of oxygen. This effect has been seen in comparisons of nose-breathing and tracheotomized guinea pigs exposed to cigarette smoke (W. C. Hulbert, unpublished data). Birds (canaries) are more sensitive than mammals to H2S: 1 00 ppm causes 1 00% mortality. It is unknown whether the mechanism is similar to that in guinea pigs or whether it is due to altered metabolic or neurological function. Extensive studies of the effects of H2S on aquatic vertebrates have been conducted (see ref. 1 4 for a review), particularly channel catfish, brown trout, walleye, northern pike, blue gill, rainbow trout, and the white sucker. H2S affects these species at all stages of development from eggs to adults, and many effects seem related to the ability of the species to express tolerance or adaptation (15). Fish reared in sublethal concentrations of H2S exhibited growth enhanced by 50 to 200% (14, 16), owing to fungicidal and bactericidal effects of HzS, similar to the effects of antibiotics normally used with captive fish. However, it was also noted that the fish were significantly less active ( 16) and showed signs of respiratory distress. Histological analysis of the gill lamellae revealed structural alterations of the gill filaments, which were

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shortened and thickened, indicating chronic irritation. Unfortunately, there have been no analyses of muscle and fat content, muscle contractility or enzyme levels, or effects of exercise, factors that may be more significant than the simple enhancement of growth. HzS becomes a major problem in fish aquaculture during harvesting (17): when anaerobic sediments of fish ponds are disturbed during netting, H2S levels throughout the water column are elevated to the toxic range. Sulfide is abundant in the marine environment (especially near volcanic vents), and many vertebrate and invcrtebrate species (e.g. crabs, clams, and tubeworms) have evolved strategies for dealing with its presence. These include sulfide detoxification in the body wall, binding and oxidation of sulfide by blood components and by cytosolic factors, oxidation by mitochon­ dria, sulfide-insensitive cytochrome c oxidase, and ATP production from sulfide oxidation (see ref. 18 for a review). Target Organ Systems Most organ systems are susceptible to the effects of HzS; therefore, this toxic gas has often been regarded as a broad-spectrum toxicant. The biological responses to H2S are dependent on the organ system; each system exhibits a different threshold responsiveness, perhaps as a function of concentration, time, or rate of exposure (19). Tissues most susceptible to H2S toxicity are those with exposed mucous membranes and those with high oxygen demands. The effects of prolonged exposure to low concentrations are not well documented. It has been proposed that the toxicity may be cumulative (20) or noncumulative (21 ) and that the effects can be completely reversible. Recov­ ery from acute intoxication is usually rapid and complete, depending upon exposure; however, some symptoms may persist (9) and some aftereffects may be irreversible as a result of secondary effects caused by lack of oxygen due to respiratory paralysis and/or pulmonary edema (7, 21). NERVOUS SYSTEM Acute exposure to HzS leads to sudden fatigue, vertigo, intense anxiety, convulsions, unconsciousness, and respiratory failure. After resuscitation, victims may suffer coordination and psychiatric disturbances, including hallu­ cinations and amnesia. Chronic exposure leads to a variety of physiological and psychological effects (see Table 2). Early neurological studies concerned the increase in respiratory rate seen in moderate HzS exposures; this increase was attributed to stimulation of peripheral chemoreceptors (6). However, little progress had been made in describing the neurological sequelae of high H2S exposure until the advent of current electrophysiological techniques.

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1 13

Brain Sulfide Content in Poisoning The sulfide (S2 -) concentration present in tissues following poisoning was unknown until recently. A recently developed, extremely sensitive (2 JLg liter-I) method (22, 23), specific to S2- and ideal for analysis of tissue, has defined the appropriate concentration of H2 S or its salts for experimental use in the brain. The method is 50-fold more sensitive than earlier methods (24). Surprisingly, both rats and humans have a relatively high endogenous level of S2-: 1. 57 JLg g- l for whole brain and 0. 67 JLg g-l in the midbrain. It would be of interest to know the S2- levels in brains of ruminants, since they produce large quantities of H2S. Recently bovine brain levels of S2 - were reported to be about 5.3 JLg g- l (24a) , although it is not known how the HPLC method used compares with the method used for rats and humans (22, 23). At the 50% lethal dose (LD50) of NaHS ( 1 5 mg kg- I) the level of S2- in rat brain was approximately 3. 1 JLg g-l (=75 JLM). By contrast, another recent method for tissue S2- analysis (25, 26) gave much lower con­ centrations in the brain. Significant to its effect on respiration, sulfide is selectively taken up by brain stem compared with other brain areas (27). Inhalation of 1600 ppm of H 2S and intraperitoneal (Lp.) injection of 30 mg of NaHS kg-1 (LDIOO doses within 4 min) produced indistinguishable increases in S2- levels in the brain (28). Brain Neurotransmitter Content Because of their essential role in central nervous system (eNS) function, the content and release of neurotransmitters during acute and chronic exposure to H2S or sulfide salts have been determined. Acute Lp. treatment with NaHS (2 x LDso) increased the concentrations of alanine, aspartate, y-aminobutyratc (GABA), glutamate, glutamine, glycine, and taurine selectively in the brain stem; minor or no changes were seen in other brain areas (29). This dose also increased serotonin (5-HT), dopamine, epinephrine, and norepinephrine levels in the brain stem, the only region where all four amine levels changed (30) These changes in catecholamine and 5-HT le vels are due to inhibition of monoamine oxidase (MAO). Acute treatment with sulfide also inhibits acetyl­ cholinesterase (3 1) and Na + IK + ATPase (see Electrophysiological Effects). Reversal of MAO inhibition was achieved ex vivo by removal of bound sulfide with the persulfide reagent dithiothreitol (32). Experimental handling of rats produced increases in brain stem glutamate, glutamine, and taurine levels. Subacute treatment with NaHS (O.5x LDso) resulted in a reduction of this stress-induced increase (33). This dose of NaHS had no effect on amino acid levels in brain stems of mice (34). Chronic exposure depressed brain amino acid transmitters (see Reproduction and Development). Therefore, it appears that degradation of amino acids (and .

1 14


amines) is inhibited by acute exposure, but that synthesis is also inhibited by chronic exposure.

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Neurotransmitter Release

Release of amino acids has been studied by push-pull perfusion (35) because of evidence that NaHS depresses synaptic transmission presynaptically (3639). Two paradigms were used: (a) NaHS (LDso) was given i.p. or (b) 3-4}oLg of NaHS ml-l (the concentration of S2- in the brain after administration of LDso) was included in the perfusion medium. Perfusates from surviving animals revealed that most changes in amino acid release in the hippocampus or caudate-putamen were immediate or delayed increases (40, 41). However, in the brain ste:m reticular nucleus, the only change was a delayed decrease in glycine release (42). These results do not provide evidence that sulfide inhibits transmission by depressing transmitter release. Electrophysiological Effects

Many in vitro neuronal preparations have been used as models in the study of the actions of sulfide, including those discussed below. Ideally, studies of respiratory rhythm generator cells would be desirable, but the technical difficulties of intracellular recording from a sufficient number of these neurons has led to the use of dorsal raphe as a typical midbrain nucleus. The use of the rat hippocampus may relate to the memory losses that are common in survivors of sulfide poisonings. In view of the changes in catecholamine levels and in acetylcholinesterase activity (3 1 ) after administration of sulfide, effects of NaBS in the frog sympathetic ganglion have been investigated by the sucrose gap method (43, 44). With this technique, arepinephrine, muscarinic and nicotinic receptors, and Na+ IK+ ATPase electrogenic pump activity can be studied (45, 46). NaHS reversibly depolarized the ganglion, but did not alter the depolarizing effect of nicotine. However, the hyperpolarizing effects of epinephrine and muscarine were both reversibly increased by NaHS. The hyperpolarizing response to pump activation did not change while NaBS was present, but was greatly potentiated after removal of the NaHS, recovering to normal after 45 min. A similar effect occurred in mammalian nl�urons (see Hippocampal CA l Neurons, below). It is remark­ able that these: neurons were exposed to sulfide for extended periods without being irreversibly damaged. It is temptilllg to suggest that the sulfide-induced depolarization is due to inhibition of the electrogenic pump, either directly or from inhibition of ATP production; however, this seems unlikely since Na+/K+ ATPAse activity in the presence of sulfide was equal to that in the control. FROG SYMPATHETIC GANGLION

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1 15

CRAYFISH SENSORY NEURON This preparation (Procambarus clarkii) was used to study the effect of sulfide on action potential (AP) generation and conduction, by using extracellular recording (47, 48). Sulfide salts «10- 4 M) caused an initial brief ( = 1 min) block of APs, then a prolonged enhance­ ment of AP amplitude, and then another brief inhibition of APs upon wash­ out. Higher concentrations of sulfide caused irreversible changes. In the absence of intracellular studies, the reason for these changes remains to be elucidated. Sulfide did not, however, alter the rate of AP conduction. This is similar to earlier results obtained with frog sciatic nerve, for which large concentrations (1-100 mM) of sulfide only slightly reduced the conduction velocity (49).

MOUSE NEUROBLASTOMA CELLS Murine neuroblastoma cells, clone NIE115 derived from sympathetic ganglia, were used to study tetrodotoxin (TTX)-sensitive Na+ channels by the patch-clamp method (50). Ca2+ and K+ currents were blocked by Cd+, Cs+ and tetraethylammonium (TEA + ) . NaHS, even as high as 10 mM, completely failed to alter the TTX-sensitive Na+ channels. As controls for sulfur-containing compounds, trials were also done with taurine and cysteic acid, neither of which alone affected the Na+ channels. It was discovered, however, that the combination of NaHS and either amino acid completely and reversibly inhibited the channels. Other sulfur-containing reagents (0.8 mM f3-mercaptoethanol and 2 mM di­ thiothreitol) inhibited Na+ channels by themselves. In in vitro situations it seems unlikely that sulfide will affect APs. However, in vivo, where free taurine levels are normally high and further increased by sulfide, taurine could play a role in H2S depression of CNS function.

CA l neurons in hippocampal slices have HIPPOCAMPAL CAl NEURONS been studied in current clamp by using potassium acetate-containing in­ tracellular electrodes (36-38; R. J. Baldelli, R. J. Reiffenstein & W. F. Colmers, unpublished data). Slices were treated with 27-200 fLM NaHS. The amplitude, duration, and threshold voltage of APs in CA l neurons were unaffected by 80 pM NaHS. The initial response of these neurons to NaHS was a rapid, reversible, concentration-dependent hyperpolarization (IH) and reduction of input resistance. Both effects were maximal at 160 fLM NaHS. The reversal potential for the conductance change was -100 mV, or slightly less than the calculated EK for these cells. An even more striking effect of NaHS was a further hyperpolarization (WaH) that occurred immediately after washout of the NaHS. This also was concentration dependent, being maximal at >200 JLM. Synaptic transmission, measured by extracellularly recorded

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population spike and EPSP field potentials, and by intracellular EPSPs, was depressed by NaHS. Pharmacological investigation of the IH and the WOH suggests that these are due to the opening of a K+ channel and to activation of Na+IK+ ATPase, respectively. Maximal responses to 200 JLM NaHS were studied (36-38; R. J. Baldelli, R. J. Reiffenstein & W. F. Colmers, unpublished data). Ex­ tracellular application of 1 JLM TTX (to block evoked transmitter release) , 1 mM 4-aminopyridine (4-AP) to block the somatic "A" and "D" K+ currents, or 30 JLM muscarine to block the voltage-dependent "M" current, did not alter the IH. However, it was reduced by 50 mM (but not 10 mM) TEA+ (36-38) and by 2 mM Cs+. Extracellular Ba2+ (1 mM), extracellular Ba2+ plus Cs + , and intracellular Cs+ blocked the IH and unmasked a depolarization response to NaHS. Conductance changes were significantly reduced only by Ba2+ or intracellular Cs+ (36; R. J. Baldelli, R. I. Reiffenstein & W. F. Colmers, unpublished data). Intracellular release of neither MgATP nor CI- reduced the IH and change in conductance. Thus, it seems reasonable that the IH is due to increased conductance of a

K+ channel. Comparison of the data with two recent compendia of K+ channels and their inhibitors (52, 53) makes it relatively easy to determine what that channel is not. It does not involve the fast transient voltage­ dependent lA, nor ID' nor the Ca2+-activated nonspecific cation channel (It), since 4-AP was ineffective, nor 1M, as muscarine did not inhibit it but Cs+ did. Because sulfide blocks oxidative phosphorylation (6), the consequent depletion of ATP could activate ATP-sensitive K+ conductances, but injec­ tion of ATP did not alter the IH. The conclusion that a gKATP is not involved must be tempered as the mechanism of K+-channel control by ATP is. not understood; this action of ATP may also be inhibited, given the number of enzymes known or inferred to be inhibited by sulfide. TEA+ blocks many K+ currents, including voltage-dependent "delayed rectifiers" and some Ca2+­

activated K+ channels (52). The cardiac-type inward rectifier (IIR) fits the antagonism data (inhibition by TEA+, Cs+, and Ba2+, but not by 4-AP). None of the procedures listed above, except intracellular Cs+ , inhibit the WOH (36-38; R. I. Baldelli, R. J. Reiffenstein & W. F. eolmers, un­ published data). Moreover, the NaHS-induced K+ conductance changes often recovered before the maximum WOH was reached. The Na+/K+ATPase inhibitor strophanthidin (3-30 JLM) did inhibit the WOH; however, this treatment depolarized the neurons, and NaHS caused further depolarization. Thus it is likely that the WOH results from activation of Na+IK+ATPase, just as in the frog sympathetic ganglion. The NaHS-induced depolarization seen in + the presence of strophanthidin suggests that sulfide does inhibit N a I + K ATPase in this preparation, although this is not so clear when using frog ganglia.



Neither did the treatments listed above affect the depression of synaptic transmission

(36-38), which suggests a presynaptic effect. However, this is

not consistent with the release experiments, evidence that depolarization by iontophoresed glutamate pulses can be inhibited

(36), or inhibition of gluta­ M. W. Wareny­

mate binding to hippocampal neuronal membranes (K. Fung, cia, S. B. Kombian

& R. J. Reiffenstein, unpublished data), all of which

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suggest a postsynaptic effect. DORSAL RAPHE NEURONS

hippocampal serotonergic


Effects of NaHS similar to those obtained in

cells have

also been

observed in


(55) dorsal raphe neurons (39). Some cells responded to NaHS

with an IH (outward current) followed by a WOH, as in CAl neurons. However, in some of these raphe neurons the IH was superimposed on a sulfide-induced depolarization (inward current). In both cases, blockade of the IH with Ba2+ plus Cs+ revealed an underlying inward current. Some neurons respondcd only with initial inward currents, followed by the same WOH. In all cases the WOH was blocked by strophanthidin. The NaHS­ induced inward currents were also occluded by the strophanthidin, showing that the depolarization was due to at least partial inhibition of Na+ IK+ ATPase by sulfide. A few neurons appeared to be unresponsive to sulfide. Although the mechanism of action of H2 S on neurons is not completely clear, sulfide can activate K+ conductances in at least two very different kinds of neurons, and these conductances are sensitive to extracellular application of Ba2+ and Cs+. Upon blockade of these K+ currents, all neurons showed a depolarizing response to NaHS, which is caused by a voltage-independent (at least in dorsal raphe neurons) inward current and which may well be due to suppression of outward current generated by the Na+ -K+ exchanger. Dorsal raphe neurons are variably affected by sulfide, perhaps reflecting the relative contributions of the Na+IK+ATPase activity and the Cs+-Ba2+-sensitive K+ conductances in their resting state. All cells that responded to NaHS also showed the outward current response to washout of NaHS. This action of sulfide on Na+ IK+ATPase in mammalian CNS neurons is rapidly and com­ pletely reversible. Clearly, other types of neurons will have to be sampled before a generalization about neural mechanisms of sulfide toxicity can be made. At present, the relatively uniform responses of hippocampal CAl neurons do suggest that inhibition may be the reason for temporary memory deficits which occur in high HsS exposure. The WOH, and potentiation of other inhibitory mechanisms, may well slow the return of function. HYPOXIA AND ANOXIA

Are the effects of H2S on nervous tissue simply

those due to inhibition of oxidative metabolism? Similar membrane potential responses to those induced by sulfide have been shown in vitro during anoxic

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or hypoxic conditions (56-60), but there seem to be pharmacological dis­ similarities. The anoxia-induced IH in hippocampal pyramidal neurons was reported to be: blocked by 4-AP (0.4 mM) (56). Another group (57) found that Ba2+ (0.5 mM) blocked the IH but that 4-AP (0.2-1.5 mM) and Cs+ (2-4 mM) were ineffective (57, 58). Neither group found TEA+ (3-10 mM) effective; however, less than 50 mM TEA+ was ineffective against NaHS (36). It has b(:en variously concluded that the anoxia-induced IH is in part due to a Ca2+ -sensitive gK (59) and also due to a muscarine- or carbachol­ sensitive gK (1M) (60). None of these anoxia data are consistent with the sulfide pharmacology. A reoxygenation hyperpolarization similar to the sul­ fide WOH has also been observed (57, 58). This also seems to be due to the electrogenic pump, since it was abolished by low K+ concentrations or I JLM ouabain. The action of sulfide is often compared to that of cyanide (6), which does block oxidative metabolism; however, on the basis of comparison of the actions of cyanide and sulfide on frog nerve (49), it has been concluded that sulfide acts by other than metabolic actions. At this time it seems that the processes caused by sulfide and simple anoxia, although producing a similar end point, are not completely identical. In view of the controversy over the actions of cyanide and sulfide and the role of chemically-induced "anoxia," it would appear essential to test the actions of cyanide in a similar manner. RESPIRATORY SYSTEM

The effects of toxic gas exposure on the respiratory system have been the focus of intensive investigations (see ref. 61 for a review). One of the hallmarks has been the change in bronchial reactivity to inhaled nonspecific agonists. Although the patterns vary, at some level of exposure there is an increase in bronchial reactivity or hypersensitivity and the expression of asthmalike responses. However, there are few animal studies and even fewer human studies that have examined this very important effect on the pulmonary system. Clinical Manifestations

In reviewing the case studies of accidental exposure, the respiratory com­ plaints are the second major group of symptoms reported after neurological ones. The most prevalent respiratory symptom following accidental exposure to H2S is dyspnea (7). In fact, dyspnea accounted for symptom complaints in 23% of 250 IhS-exposed workers who filed claims with the Workers' Health and Safety Compensation Board in Alberta, Canada. Other prevalent symp­ tomatic complaints in that study were sore throats, coughs, and chest pain. In nine of thesle workers given pulmonary function tests, three showed an obstructive pattern. Other respiratory signs and symptoms seen less frequently



were pulmonary edema, cyanosis, and hemoptysis. One of the complications following exposure to

H2S is the development of pneumonia, which may be

related to the inhibitory effect of H2S on alveolar macrophages and their subsequent ability to inactivate bacteria


Only one study has evaluated the effccts of environmcntal levels of H2S on pulmonary function

(8). This was an examination of the effects of living

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downwind from a natural-gas refinery. Although the investigations did not assess hypersensitivity by challenge with either

H2S or a nonspecific agonist

such as methacholine, they did show that there was an excess of respiratory symptoms in the exposed area, especially in children from 5 to

13 years of age

and in never-smokers over 14 years of age. Unfortunately, their study did not assess the direct effects of HzS, but, rather, those of the combined emissions from the gas refinery. A recent study

(63) evaluated the effects of inhaling H2S, 2 ppm for 30

min, on pulmonary function in a cohort of pulp mill workers who either were asymptomatic for asthma or had symptoms of asthma. No effect on airway resistance or specific airway conductance in the asymptomatic workers was found. In the asthmatic subjects there were nonsignificant increases in air­ ways resistance (26.3%) and decreases in specific airway conductance (8.4%). The investigators concluded that exposure for a relatively short time to H2S concentrations appreciably higher than those existing in ambient air in the pulp mill does not cause noticeable effects on respiratory function; however, in

2 of the 10 asthmatic subjects, changes greater than 30% in both

resistance and conductance were found, indicating airflow obstruction. These results must be evaluated in light of two factors. First, no non-pulp mill workers were included in the study. Second, as it is known that a self selection takes place in workers in the pulp and paper industry, such that only those who can tolerate the fumes work in the environment

(64), this may

significantly pre-bias any results. It is significant that symptoms of obstructive air flow only occurred in the asthmatics. One might speculate that in a more normal population, there may be more responses to the inhalation of H2S in asthmatic subjects, consistent with their hypersensitivity to toxic gases. To date, there have been no pulmonary function studies evaluating a cross-section of the general popula­ tion to exposure to H2S. Until that is done, the effects of H2S on pulmonary function and bronchial reactivity in humans will remain speculative.

Animal Studies There have been two major animal studies that have examined the acute and subchronic effects of inhaling H2S on pulmonary function, bronchial reactiv­ ity, and lung histology (65-70). The subchronic experiments were designed to


REIFl::900 ppm) levels of H2S. An increase in a variety of hematological parame­ ters, but a decrease in erythrocyte numbers in mice exposed to H2S have been reported

(100). In contrast, other studies (97) observed no changes in the

hematological parameters following chronic exposure to H2S at 10-80 ppm. A decrease in enzymatic activities associated with heme synthesis occurs in humans exposed to H2S plus methylmercaptan during wood pulp production



(101, 102). Results of interaction of H2S with hemoglobin to produce sulfhe­ moglobin are also contradictory (5, 6).

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Immune System

There are a few studies which suggest that H2S interferes with the immune system. It was concluded in one study involving Staphylococcus challenge in rats exposed to 45 ppm of H2S that secondary infection due to depression of macrophage function may occur following H2S exposure (62). This was recently confirmed in an epidemiology study (8) . The possibility of allergic or enhanced anaphylactic response has also been implicated in one early study (6), but the response in rabbits was opposite to that in guinea pigs; this creates some doubt about the validity of the results and their interpretation. Endocrine System

Possible alteration of endocrine functions has also been suggested by a decrease in milk production in cows exposed to 20-50 ppm of H2S and by a 50% increase in plasma cortisol levels in goats at 100 ppm. Dose-dependent lesions of rat thyroid gland following administration of 14-28 ppm of H2S have also been reported (6). Psychological Effects

Behavioral and psychological effects of H2S (see Table 2) have been dis­ cussed in several earlier studies , and there is a recent report of persistent cognitive impairment of three patients following acute exposure to H2S (103). A recent case of "knockdown" (unconsciousness) resulted in permanent retrograde amnesia (I. M. O. Vicas, personal communication) . The offensive odor is often interpreted as dangerous or life-threatening, and this could induce a variety of both psychological and neurophysiological reactions . Carcinogenesis

There has been very little activity in research concerning the carcinogenic , mutagenic, or teratogenic effects of H2S in humans and other animals; the reported genotoxic effects may be limited to cytotoxicity (6). Further in­ vestigations in validated test systems are obviously required. CLINICAL APPLICAnONS

Diagnosis of exposure to H2S is usually a matter of circumstance. There are a wide variety of symptoms (Table 2), not all of which may be present.

1 28


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Table :�

Clinical symptoms after H2S exposure' Depression

"Felt ill"


Visual "fogging"




Sore throat/cough



Chest pain





Eye pain


Pulmonary edema





Abnormal peripheral reflexes


Anorex ia

Weakness of extremities



Compiled from several sources (2, 7, 108).

Forensic Detection of H2S Poisoning

Confirmation of sublethal exposure has been difficult until the recent develop­ ment of a simple method for detecting blood sulfide levels (105) . Even so, the procedure is too long to provide rapid diagnosis. Sulfide levels are still elevated in blood samples taken 2 hr after exposure (101, 102). In addition, some enzyme levels remain depressed long after the exposure ( 1 0 1 , 1 02). After lethal exposures, the brain sulfide content can now be measured for forensic purposes (22, 23). To date this procedure has been used to determine the cause of death in four cases of suspected H2S poisoning (106); one of these was determined not to directly involve H2S. The use of dithiothreitol in this test should improve the differentiation betwcen normal and poisoned individuals, although this has only been tried in animals thus far (32). Therapeutic Management of H2S Poisoning

The initial events in recovery are the most important, and immediate removal to fresh air is paramo unt (but inadequately equipped rescuers often become victims). Most victims, even though they may be unconscious, appear to recover spontaneously if they are breathing. If they are not, assisted breathing should be instituted immediately, with full cardiopulmonary resuscitation if there is no heartbeat (107). Given the low level of H2S exhaled, there would appear to be no danger to the rescuer in the use of mouth-to-mouth respiration (107). Only then should other measures be instituted. Two such approaches have been advocated: scavenging sulfide with methemoglobin formed oy administration of nitrites, and administration of hyperbaric oxygen. Nitrite does protect against subsequent poisoning in animals (108), but there are few cases in which treatment after exposure can be shown to have affected the outc e. One early survey (109) suggested that nitrites were of little use. Four ecent case reports (1 1 0-1 13) give conflicting evi-





dence of the value of nitrites. It has been suggested (5) that nitrites may be of use only if given within minutes after the H2S exposure. Although nitrite did protect against sulfide toxicity, the same study showed that 100% O2 at atmospheric pressure had no beneficial effect ( l 08) . There are two case reports of the use of hyperbaric O2 therapy ( l 12, 1 13) (in which nitrites were also used). In the first there was evidence of pulmonary edema, when the hyperbaric O2 undoubtedly increased O2 deliv­ ery. In the latter case, after extensive but ineffective treatment with nitrites, 1 2 treatments with hyperbaric oxygen were given over 6 days before the patient was asymptomatic. This cannot be distinguished from normal recov­ ery. One other patient (I. M. O. Vicas, personal communication) was uncon­ scious for several hours and regained consciousness during hyperbaric oxygen therapy; however, this individual had severe, apparently permanent, retro­ grade amnesia. Although this therapy is modeled after treatment for cyanide poisoning (113), it is still unclear whether hyperbaric oxygen affects the outcome of H2S poisoning (107). Even if the increased partial pressure of the oxygen competitively reactivated oxidative cytochromes, as has been sug­ gested (113), it is possible that the action of ATP thus produced is still inhibited by sulfide.

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Some enzymes remain inhibited far beyond the time to apparent recovery, e. g. some blood enzymes returned to normal only 2 months after the H2S poisoning (101, 102). This suggests that some of the sulfide remains firmly bound and is not removed by lowering the plasma sulfide levels by scavenging or metabolism. It should be possible to actively remove this HS- ion by persulfide reagents. Dithiothreitol given 20 min before NaHS provided significant protection in rats (32, 44); however, death was too rapid for this agent to provide resuscitation if given after the NaHS. Dithiothreitol administration increases the amount of sulfide recovered from the brain tissue of poisoned animals and reverses the inhibition of MAO by HS- (32). It also restores contractile function in oxidant-injured cardiac muscle (114). This might be doubly useful, since the 1975 report of increased cardiovascular mortality among workers exposed to H2S (98) has recently been confirmed (9), and there are a number of reports of prolonged arrhyth­ mias following exposure of animals to H2S (6; see also Cardiovascular System). Interventions that actively remove sulfide from the sites causing inhibition of enzymes, or altered control of ion channels, should hasten recovery. Antidotes suitable for use in the field, especially in situations in which almost immediate death occurs, are unlikely to be found (5). However, in cases of extended unconsciousness , when the victims are hospitalized while still alive, this approach should be considered.




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SUMMARY Significant progress had been made in determining the action of sulfide on the primary targ(�t organs. It is reasonably clear that sulfide causes both K+­ channel-mediated hyperpolarization of neurons and potentiation of other in­ hibitory mechanisms. It is not clear whether these processes are similar to those that occur in anoxia. Changes in perinatal and adult brain neurotransmit­ ter content and release may be related to clinical impairment of cognition. H2S exposure:s at concentrations below the current occupational limits cause physiological changes in pulmonary function, thus suggesting that asthmatics are at risk. Studies of fetal and neonatal brain tissue have shown an abnormal development, and the long-term consequences of these neuronal changes have not yet been assessed. Finally, new approaches to therapy are required, such as the use of agents that actively remove sulfide from its sites of action. This may prove more useful in preventing some of the long-term adverse sequelae than the use of nitrites and hyperbaric O2, although the latter should be used in cases of pulmonary edema. ACKNOWLEDGMENTS

We thank the various agencies which have supported our research: Alberta Occupational Health and Safety; Alberta Lung Association; Alberta Heritage Foundation for Medical Research; Medical Research Council of Canada; and members of the Canadian Petroleum Association. We are also indebted to the many participants in the International Conference on Hydrogen Sulphide Toxicity, Banff, 1989. Literature Cited 1 . Ramazzini, B . 1 7 1 3 .

Diseases of Work­ ers. (Trans\. from the Latin text De Mor­




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effects of oxygen,


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Toxicology of hydrogen sulfide.

Significant progress has been made in determining the action of sulfide on the primary target organs. It is reasonably clear that sulfide causes both ...
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